重组人血管内皮抑制素对小鼠肿瘤和心肌中血管结构及血管生成相关因子表达的影响  

Comparison of the effect of rh-endostatin on intratumoral and myocardial micrangium in mice

作　　者：张翠翠[1] 李凯[1] 魏熙胤[2] 陈程[1] 袁静[1] 王晶[1] 

机构地区：[1]天津医科大学附属肿瘤医院肺部肿瘤内科,300060 [2]天津医科大学附属肿瘤医院中心实验室,300060

出　　处：《中华肿瘤杂志》2011年第6期415-420,共6页Chinese Journal of Oncology

基　　金：天津市医科大学科研项目（2009ky37）;CSCO血管靶向罗氏基金科研计划项目（Y-X2011-001）

摘　　要：目的观察重组人血管内皮抑制素对小鼠肿瘤及心肌中微血管影响的差异。方法40只小鼠随机分为空白对照组（未荷瘤，生理盐水100ml／d）、药物对照组（未荷瘤，重组人血管内皮抑制素400μg／d）、模型组（荷瘤，生理盐水100μl／d）和实验组（荷瘤，重组人血管内皮抑制素400μg／d），分别处理28d。实验前后称量小鼠体重，测量移植瘤体积。采用免疫组化法检测小鼠心脏和移植瘤组织中基质金属蛋白酶（MMP）-2、MMP-9、缺氧诱导因子1α（HIF—1α）以及血管内皮生长因子（VEGF）蛋白的表达情况，计数微血管密度（MVD）。以CD34与Masson双染法观察微血管结构的变化。结果实验组小鼠肿瘤体积的增加值为（48．18±37．31）mm^3，低于模型组[（113．80±73．27）mm^3，P〈0．05]；各组小鼠体重变化的差异无统计学意义（P〉0．05）。应用重组人血管内皮抑制素后，移植瘤组织中MMP-9和VEGF蛋白的表达显著降低，移植瘤组织中MMP-2、HIF-1α以及心肌组织中MMP-2、MMP-9、HIF—1α和VEGF蛋白的表达均无显著变化；移植瘤组织的MVD显著降低，胶原覆盖血管的比例升高，而心肌组织的MVD和结构几乎无变化。结论重组人血管内皮抑制素可通过下调移植瘤组织中MMPs和VEGF蛋白的表达，降低MVD，抑制移植瘤的生长，并可使移植瘤血管趋向成熟，但不能降低心肌组织中MMPs的表达和成熟血管的MVD。Objective To compare the effect of rh-endostatin on micrangium in tumor and myocardial tissue in nude mice. Methods Nude mice were randomized into 4 groups （ 10 mice in each group）, blank control group （without tumor burden, received NS 100 μl·d^-1 injection）, drug control group （without tumor burden, received rh-endostatin 400 μg · d^-1 injection）, model group （with tumor burden, received NS 100 μl·d^-1 injection） and treatment group （with tumor burden, received rhendostatin 400 μg · d^-1 injection） for 28 days. The tumor volume and body weight of the mice were measured before and after administration. The expression of CD34, MMP-2, MMP-9, HIF-1α and VEGF in the myocardium and tumor were detected by immunohistochemistry. The vascular structure was observed by immunoenzymatic CD34 and Masson double staining. Results The increase of tumor volume of the treatment group[ （48.18 ± 37.31 ） mm^3 ] was significantly lower than that in the model group [ （ 113.80 ±73.27） mm^3 ）. The changes of body weight was not significant different among the four groups. After treated with rh-endostatin, the expressions of MMP-9 and VEGF in tumors were significantly down-regulated, but the expressions of MMP-2 and HIF-1α in the tumor were not. The microvessel density （MVD） in the tumors of treatment group was significantly decreased compared with that of model group. The proportion of tumor vessels covered by collagen in the treatment group was increased compared with that of the model group. However, MVD and micrangium in myocardium were not changed significantly. Conclusion Rh-endostatin can decrease the expression of MMP-9, VEGF and MVD, inhibit the tumor growth and normalize tumor micrvangium in tumor but not weaken the MMPs and MVD of mature micragium in myocadium.

关 键 词：重组人血管内皮抑制素 移植瘤组织 心肌组织 微血管 小鼠 

分 类 号：R96[医药卫生—药理学]